Despite advances in the discovery of antitumor agents, cancer remains a disease with very poor prognosis. Substances displaying in vitro and in vivo anticancer activity are continuously reported in the literature, but only a scant number of those substances go past a phase II clinical trial. Moreover, the cure rates of drugs for the treatment of cancers are unacceptably low, and the side effects of these drugs are severe. The toxic effects of the drugs on the cancer tissues only marginally exceed their toxic effects on normal, healthy cells of the body that should be protected from the effects of the drugs. Moreover, that high failure rate of potential anticancer agents arguably can be traced to the lack of methods to ascertain and to design into, in advance, control of secondary effects, specificity, and high target-tissue activity in human subjects. A design process is needed to design into candidate compounds all the requirements for the drug delivery system and anticancer effectiveness. That goal is achieved by the present invention.
Chemotherapy research in cancer treatment has been largely devoted to the search for drugs providing toxin specificity to destroy neoplastic tissue in the body without exceeding toxic exposure levels injurious to healthy tissues, that is to say, to the search for cytotoxic drugs that concentrate in neoplastic tissues, or for drugs that metabolize into such toxins. Although major efforts to this end have been made, success has been achieved for only a few cancer types. For most cancer types, success has been quite limited.
Modem anticancer drug development began with the recognition that some poison gas exposures in WWI actually had anticancer side effects. The process of anticancer drug development began at this point with the mostly random procedure of searching through known toxins to determine through exposure if the given toxin had differential toxicity that would aid in the control or cure of cancer. The approach centered on the discovery of xe2x80x9csingle moietyxe2x80x9d compounds.
In the 1930s, more complex compounds were developed so designed as to divide the function of the anticancer agent into two parts, or two moieties on the same compound, wherein one moiety would serve to concentrate the drug in the cancer cell or tissue and the second moiety would serve to destroy the cancer cells wherein the compound concentrated. A fundamental advance in this area was the elucidation of chemical entities with tumor tissue selectivity. Early reports on such selectivity were made for the dye Nile blue by Lewis, et al. in Cancer Res. 9:736, 1949, a report that prompted the modification of this benzophenoxazine to incorporate a toxin such as a nitrogen mustard as an integral part of the molecule (Sen, et al. in Int. Union against Cancer Acta, 26, 774 (1960)). Those attempts at modification of a tumor tissue selective agent with a toxic moiety met with limited success. It has been presumed that the failure of such approaches is due to intrinsic modification of the tissue selectivity of the parent compound with the addition of the toxic moiety. The cause of the failure, however, is more fundamental and is shared by other drug delivery concepts, in particular, the concept of anticancer prodrugs.
Beginning in the early 1950s, the two-moiety drug design approach of a concentrating moiety and a toxic moiety was modified to the two-moiety xe2x80x9cprodrugxe2x80x9d design, wherein one moiety served to modify or xe2x80x9cmaskxe2x80x9d or xe2x80x9ccapxe2x80x9d the toxicity of the second toxic moiety of the drug compound until the drug entered the cancer cells. At this point, a chemical reaction, generally intended to be with enzymes specific to the cancer cells, would remove the mask or cap moiety so that the toxic moiety would kill the cancer cells. Again, the prodrug anticancer delivery concept has had limited success.
Both the concept of drugs that combine a concentrating moiety together with a toxic moiety and the concept of prodrugs that are to be metabolized preferentially in cancer tissues suffer from the problems that arise out of the nature of cancer itself: cancer cells and tissues are not foreign biological organisms having a chemistry distinct from normal tissue. These tissues are, in the case of human cancers, human tissues. The normal and neoplastic tissue have essentially the same chemistry; that is, for the most part, both consist of the same chemical molecules and in similar concentrations.
In 1980, Evan Harris Walker in Perspectives in Biology and Medicine, Spring Issue, 424-438, (1980) argued that the prodrug concept and the combination of toxin with concentrator concept fail because of the fundamentals of the pharmacokinetics of drug delivery. The time course of the drugs depends on their metabolic uptake and elimination rates. If the rates are lower for the cancer cells than for the normal cells, the drugs will appear to concentrate. That is to say, after a sufficient lapse of time, the drugs will have been metabolized and eliminated out of the normal tissues while still being in significant concentrations in the cancer cells and tissues. This will be the case even though the total amount of drug delivered to both normal and cancer cells may be essentially the same. The problem of achieving an effective anticancer drug was not one of achieving differential concentration, or of having the drug be activated by enzymes in the cells, but rather one of being able to suppress the toxicity of the drug in the normal cells and tissues until the differential concentration of the drug had become favorable.
In order to take advantage of the drug concentration differential between normal and cancer tissue, Walker in Perspectives in Biology and Medicine, Spring Issue, 424-438, (1980) proposed a design procedure consisting of two drugs, a prodrug and an xe2x80x9cactivationxe2x80x9d drug. Both the prodrug (that had a design limited to a toxin plus a cap or mask moiety) and the activation drug were to be designed so as to have little or no toxic or other effect on the body (i.e., to be substantially biologically inert) if administered alone. However, in combination, these two compounds would react in the body to produce a compound toxic to the cells wherein it was produced. These two drugs were to be administered sequentially with a time delay between their introduction to allow for the normal cells to metabolize and eliminate the prodrug out of the body before the activation drug was administered. At that point in timexe2x80x94after a time delay for differential delivery of the drugxe2x80x94differential concentration of the prodrug would have been achieved. Removing the masking or capping moiety of the prodrug at that timexe2x80x94when the prodrug would be differentially concentrated in the cancer tissuesxe2x80x94would then result in delivery of high levels of the included anticancer toxin. In this way, anticancer toxins would be delivered to cancer cells and tissues without harm being done to normal cells and tissues.
Prodrugs of the type proposed by Walker were designed and synthesized by the present inventors. One of these was a 5-fluorouracil-N-glucoside, which can be activated by the enzyme xcex2-glucosidase. After designing a prodrug of this type, the inventors of the present disclosure found that a more complex prodrug and activation drug system would be needed to provide all the requirements for a selective and effective anticancer pharmaceutical. In particular, the present inventors found that the prodrug and activation design of this type also had limitations in that the differential concentration achievable within the limits of that design was not sufficiently high. In other words, the differential concentration effect due entirely to differential diffusion with no added moiety to enhance the concentration differential proved to be inadequate. A more complex drug system was needed and it was found that a process for the development of the drug system would be required.
The present disclosure covers an assemblage containing chemicals and chemical moieties, a process for the detailed design of an assemblage, products or devices needed to carry out and evaluate the process, chemical systems designed by the process that serve as specific assemblage examples, and procedures needed for the successful use of an assemblage and the specific examples of assemblages designed by the process disclosed herein.
The assemblage covered by the present disclosure is herein defined as a complex proto-drug and activation drug system. The proto-drug includes one or more differentially selective moieties, one or more toxic moieties, and one or more moieties that serve the purpose of providing a xe2x80x9cmaskxe2x80x9d or xe2x80x9ccapxe2x80x9d to the toxic moieties.
The present disclosure also covers an activation drug, herein defined as one or more chemicals serving the function of activating the proto-drug of the assemblage. The activation drug removes the mask or cap moiety, or a sufficiency of the mask or cap, or so modifies the chemistry of the overall proto-drug molecule as to substantially eliminate the masking or capping function of the mask or cap, thereby making the resulting compound a toxic, pharmacologically active agent. In addition, the present disclosure covers the introduction of xe2x80x9clinksxe2x80x9d that serve the purpose of chemically tying the moieties of the proto-drug together so as to form a single compound, that alone is substantially biologically inert. The links may be the chemical bonds between the linked moieties or a combination of atom(s) and bonds that connect the moieties of the proto-drug.
The present disclosure also covers a process whereby the proto-drug and activation drug system (i.e., the assemblage) is to be designed and specified. That is to say, the likelihood that such a complex system of chemicals having the set of required properties could be obtained through chance experimentation alone is nil. As a result, it is necessary to develop a process whereby such chemical systems can be produced.
The present disclosure also covers novel products or devices used in the present process.
The present disclosure also covers specific examples of proto-drug and activation drug systems (i.e., assemblages) as produced by the successful use of the process.